Gender differences in the immune response are particularly evident in autoimmunity where females show increased susceptibility for developing autoimmune disease but males are predisposed to a poorer prognosis. This sex-based divergence in both disease susceptibility and disease outcome is not well understood yet is clearly evident in several diseases having prominent autoimmune features, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Graves' disease, and DCM. The experiments proposed in the current application are designed to address the basis for the differential prognosis of males versus females with autoimmune disease. To this end we have developed a murine EAMC model in which male SWXJ mice show prolonged maintenance of cardiac self- recognition and develop a high incidence of DCM, whereas female mice show aborted maintenance of T cell autoimmune memory and significant protection from the development of DCM. Thus, we hypothesize that the poor prognosis in males with autoimmune disease is due to their enhanced ability to maintain autoimmune T cell memory and persistence of inflammatory self-recognition. In Specific Aim 1, we will determine the mechanism by which differential gender- based maintenance of self-recognition occurs in male versus female SWXJ mice with EAMC. In Specific Aim 2, we will determine how the patterns of autoimmune memory may be altered by immune and non-immune manipulations. In addition, we will determine whether persistence of memory causes DCM and whether the gender-based differential development of autoimmune memory may be therapeutically manipulated to alter disease outcome. We believe that our proposed studies will lead to a better understanding of how autoimmune memory is maintained or aborted by gender-defined conditions. Such information may ultimately serve as a basis for therapeutic intervention during the development of autoimmune disease.